US8916708B2 - Urea derivatives and their therapeutic use in the treatment of, inter alia, diseases of the respiratory tract - Google Patents
Urea derivatives and their therapeutic use in the treatment of, inter alia, diseases of the respiratory tract Download PDFInfo
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- US8916708B2 US8916708B2 US13/701,989 US201113701989A US8916708B2 US 8916708 B2 US8916708 B2 US 8916708B2 US 201113701989 A US201113701989 A US 201113701989A US 8916708 B2 US8916708 B2 US 8916708B2
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- LJPHMZLOHHLBAA-UHFFFAOYSA-N [CH2-][C+]1CCC[C+]([CH2-])CC1.[CH2-][C+]1CC[C+]([CH2-])C1.[CH2-][C+]1CC[C+]([CH2-])CC1 Chemical compound [CH2-][C+]1CCC[C+]([CH2-])CC1.[CH2-][C+]1CC[C+]([CH2-])C1.[CH2-][C+]1CC[C+]([CH2-])CC1 LJPHMZLOHHLBAA-UHFFFAOYSA-N 0.000 description 1
- NTHQAVVMXDNRRA-UHFFFAOYSA-N [CH2-][C+]1C[C+]([CH2-])C2=C1C=CC=C2 Chemical compound [CH2-][C+]1C[C+]([CH2-])C2=C1C=CC=C2 NTHQAVVMXDNRRA-UHFFFAOYSA-N 0.000 description 1
- SKISFFQJYJNSPV-YBUXHFHDSA-N [CH2][Y][C@@H]1CC[C@@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@@H]1CC[C@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@@H]1C[C@@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@@H]1C[C@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@H]1CCC([NH2+][CH2-])C2=C(C=CC=C2)C1.[CH2][Y][C@H]1CC[C@@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@H]1CC[C@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@H]1C[C@@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@H]1C[C@H]([NH2+][CH2-])C2=C1C=CC=C2 Chemical compound [CH2][Y][C@@H]1CC[C@@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@@H]1CC[C@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@@H]1C[C@@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@@H]1C[C@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@H]1CCC([NH2+][CH2-])C2=C(C=CC=C2)C1.[CH2][Y][C@H]1CC[C@@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@H]1CC[C@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@H]1C[C@@H]([NH2+][CH2-])C2=C1C=CC=C2.[CH2][Y][C@H]1C[C@H]([NH2+][CH2-])C2=C1C=CC=C2 SKISFFQJYJNSPV-YBUXHFHDSA-N 0.000 description 1
- POPGQQXRWUVJCN-VHSXEESVSA-N [N-]=[N+]=N[C@H]1CC[C@@H](O)C2=C1C=CC=C2 Chemical compound [N-]=[N+]=N[C@H]1CC[C@@H](O)C2=C1C=CC=C2 POPGQQXRWUVJCN-VHSXEESVSA-N 0.000 description 1
- POPGQQXRWUVJCN-UWVGGRQHSA-N [N-]=[N+]=N[C@H]1CC[C@H](O)C2=C1C=CC=C2 Chemical compound [N-]=[N+]=N[C@H]1CC[C@H](O)C2=C1C=CC=C2 POPGQQXRWUVJCN-UWVGGRQHSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- R 6 is independently H, C 1 -C 6 alkyl, hydroxyl or halo; wherein in formulae (IVa), (IVb) and (IVc) n and p are as defined above; and wherein in R 6
- hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
- organic acids e.g. with acetic, trifluoroacetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.
- Y is prefereably —O—.
- the compounds with which the invention is concerned are p38 kinase inhibitors, and are useful in the treatment of several diseases for example inflammatory diseases of the respiratory tract.
- diseases for example inflammatory diseases of the respiratory tract.
- diseases include asthma, rhinitis, allergic airway syndrome, bronchitis and chronic obstructive pulmonary disease.
- a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI).
- DPI dry powder inhaler
- flash silica refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution or use of the CombiFlash® Companion purification system or use of the Biotage SP1 purification system. All solvents and commercial reagents were used as received.
- (R)-3-amino-indan-1-one (EP1316542A1) was prepared from (R)—(N-acetyl)- ⁇ -alanine as described in EP1316542A1 . Bioorg. MedChem. Lett, 2008, 18, 4224-4227 and Chem. Lett., 2002, (3), 266.
- (1R,3R)-3-amino-indan-1-ol was prepared from (R)-3-amino-indan-1-one using proceedures described in WO2008/043019. The title compound was prepared using (1R,3R)-3-amino-indan-1-ol in a similar manner to Example 1, steps e and f.
- Example 20 step a (381 mg, 1.02 mmol), Example 2 step b (183 mg, 1.12 mmol), potassium tert-butoxide (125 mg, 1.12 mmol) and DMPU (492 ⁇ L, 4.08 mmol) was heated at 50° C. for 2 h then at 80° C. for 1.5 h.
- the reaction mixture was cooled to RT and partitioned between H 2 O-EtOAc.
- the organic layer was dried over MgSO 4 , filtered and concentrated in vacuo.
- the residue was purified by FCC using 2M NH 3 -MeOH in DCM (0 to 50%) to give the title compound (146 mg, 28%).
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
wherein n is 1 or 2; and R3 and R4 are independently H or C1-C6 alkyl, or R3 and R4 taken together with the nitrogen to which they are attached form a 6-membered heterocyclic ring optionally containing a further heteroatom selected from N and O;
while any other occurrence of R6 is independently H, C1-C6 alkyl, hydroxyl or halo;
wherein in formulae (IVa), (IVb) and (IVc) n and p are as defined above; and wherein in R6
Compound of the invention | 24 | mg/canister | |
Lecithin, NF Liq. Conc. | 1.2 | mg/canister | |
Trichlorofluoromethane, NF | 4.025 | g/canister | |
Dichlorodifluoromethane, NF | 12.15 | g/canister. | |
wherein Rb is as defined for R2 in general formula (I), in a suitable solvent such as dimethyl sulfoxide, 1,4-dioxane or acetonitrile, in the presence of a base such as diisopropylethylamine at a range of temperatures, preferably between room temperature and 100° C.
wherein Rc may be a suitable protecting group by deprotection according to methods known to those skilled in the art.
by reaction with an aldehyde of general formula (I):
RaCHO (I),
in a suitable solvent such as ethanol or tetrahydrofuran at a range of temperatures, preferably between room temperature and 80° C.
using a suitable dehydrating agent such as Burgess' reagent, triphenyl phosphine and hexachloroethane, phosphorus oxychloride, acetic acid or Mitsunobu conditions (diethylazodicarboxylate/triphenylphosphine/trimethylsilylazide), in the absence or presence of a suitable solvent such as tetrahydrofuran, toluene or NMP, at a range of temperatures, preferably between room temperature and 120° C.
RaCO2H (o),
using a suitable acylating/dehydrating agent such as triphenylphosphine/trichloroacetonitrile in the presence of a base such as diisopropylethylamine, in a suitable solvent such as dichloromethane or acetonitrile, at a range of temperatures, preferably between room temperature and 150° C.
General Experimental Details
Gradient - Time | flow mL/min | % A | % B | |
0.00 | 2.0 | 95 | 5 | |
0.50 | 2.0 | 95 | 5 | |
4.50 | 2.0 | 5 | 95 | |
5.50 | 2.0 | 5 | 95 | |
6.00 | 2.0 | 95 | 5 | |
Detection - MS, ELS, UV (200 μL split to MS with in-line HP1100 DAD detector). | ||||
MS ionization method - Electrospray (positive and negative ion). |
Method 2
Gradient - Time | flow mL/min | % A | % B | |
0.00 | 2.0 | 95 | 5 | |
0.50 | 2.0 | 95 | 5 | |
4.50 | 2.0 | 5 | 95 | |
5.50 | 2.0 | 5 | 95 | |
6.00 | 2.0 | 95 | 5 | |
Detection - MS, ELS, UV (200 μL split to MS with in-line Waters 996 DAD detector). | ||||
MS ionization method - Electrospray (positive and negative ion). |
Method 3
Gradient - Time | flow mL/min | % A | % B | |
0.00 | 2.0 | 95 | 5 | |
0.50 | 2.0 | 95 | 5 | |
4.50 | 2.0 | 5 | 95 | |
5.50 | 2.0 | 5 | 95 | |
6.00 | 2.0 | 95 | 5 | |
Detection - MS, ELS, UV (200 μL split to MS with in-line HP1100 DAD detector). | ||||
MS ionization method - Electrospray (positive and negative ion). |
Method 4
Gradient - Time | flow mL/min | % A | % B | |
0.00 | 1.0 | 85 | 15 | |
1.00 | 1.0 | 85 | 15 | |
13.00 | 1.0 | 5 | 85 | |
20.00 | 1.0 | 5 | 85 | |
22.00 | 1.0 | 85 | 15 | |
Detection - MS, UV PDA. | ||||
MS ionization method - Electrospray (positive and negative ion). |
Method 5
Gradient - Time | flow mL/min | % A | % B | |
0.00 | 0.4 | 95 | 5 | |
0.40 | 0.4 | 95 | 5 | |
6.00 | 0.4 | 5 | 95 | |
6.80 | 0.4 | 5 | 95 | |
7.00 | 0.4 | 95 | 5 | |
8.00 | 0.4 | 95 | 5 | |
Detection - MS, UV PDA. | ||||
MS ionization method - Electrospray (positive and negative ion). |
Method 6
Example | |||
No. | Structure | NMR (400 MHz) δ | LCMS |
3 |
|
(CDCl3): 1.31 (9H, s), 1.80- 1.93 (1H, m), 1.94-2.09 (2H, m), 2.17-2.28 (1H, m), 2.36 3H, s), 4.99-5.09 (1H, m), 5.10-5.18 (2H, m), 6.18 (1H, s), 6.24 (1H, s), 7.11 (1H, dd, J 2.0, 8.0), 7.17-7.31 (6H, m), 7.34-7.40 (3H, m), 7.44- 7.61 (3H, m), 7.67 (1H, dd, 1.6, 7.6), 7.72-7.76 (1H, m). | (Method 5): Rt 5.22 min, m/z 646[MH+]. |
(+/−)1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[3-(2-chloro-phenyI)-[1,2,4]triazolo[4,3- a]pyridin-6-yloxy]-cis-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea | |||
4 |
|
(d6-DMSO) 1.26 (9H, s), 1.75-2.10 (4H, m), 2.35 (3H, s), 4.73-4.81 (1H, m), 5.48- 5.53 (1H, m), 6.31 (1H, m), 7.05 (1H, d, J 8.0), 719-7.38 (9H, m), 7.67-7.78 (3H, m), 7.89 (1H, d, J 12.0), 7.96 (1H, s), 8.03 (1H, s) | (Method 5): Rt 5.30 min, m/z 680 [MH+]. |
(+/−)1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-{4-[3-(2,6-dichloro-phenyl)[1,2,4]triazolo[4,3- a]pyridin-6-yloxy]-cis-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea | |||
5 |
|
(d4-MeOH) 1.32 (9H, s), 1.66-1.98 (4H, m), 2.40 (3H, s), 4.73-4.84 (1H, m), 5.13 (1H, t, J 4.7), 5.19 (2H, s), 6.35 (1H, s), 7.04-7.40 (18H, m), 7.60-7.68 (3H, m), 7.73 (1H, d, J 9.5) | (Method 4): Rt 12.5 min, m/z 717 [MH+]. |
(+/−) 1-{4-[3-(2-Benzyloxy-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxyl-cis-1,2,3,4- tetrahydro-naphthalen-1-yl}-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-urea | |||
6 |
|
(d6-DMSO): 1.28 (9H, s), 1.38 (6H, t, J 7.2), 1.85-2.22 (4H, m), 3.57 (q, 1H, J 6.6), 4.87-4.95 (1H, m), 5.55 (1H, t, J 4.17), 6.40 (1H, s), 7.02 (1H, d, J 9.0), 7.22 (1H, dd, J 10, 2.4), 7.27-7.45 (4H, m), 7.69 (1H, d, J 10.0), 8.21- 8.24 (1H, m), 9.32 (1H, s). | (Method 5): Rt 4.35 min, m/z 488 [MH+]. |
(+/−) 1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6- yloxy)-cis-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea | |||
TABLE 1 | ||
Example | p38α inhibition | |
Example 1 | ++++ | |
Example 2 | ++++ | |
Example 3 | ++++ | |
Example 4 | ++++ | |
Example 5 | +++ | |
Example 6 | ++++ | |
Example 7 | ++++ | |
Example 8 | ++ | |
Example 9 | ++ | |
Example 10 | ++++ | |
Example 11 | ++++ | |
Example 12 | ++ | |
Example 13 | ++++ | |
Example 14 | + | |
Example 15 | + | |
Example 16 | ++++ | |
Example 17 | ++++ | |
Example 18 | +++ | |
Example 19 | +++ | |
Example 20 | ++++ | |
Example 21 | NT | |
Example 22 | ++++ | |
In the table above, p38α binding potencies (IC50 values) are indicated as follows: <7000-500 nM ‘+’; <500-100 nM ‘++’; 10−<100 nM ‘+++’; <10 nM ‘++++’. | ||
All compounds tested exhibited IC50 values <7000 nM. NT not tested. |
p38 Functional Assay
TABLE 2 | ||
Example | EC50 (THP-1) | |
Example 1 | ++++ | |
Example 2 | ++++ | |
Example 3 | ++++ | |
Example 4 | ++++ | |
Example 6 | ++++ | |
Example 7 | ++++ | |
Example 10 | ++++ | |
Example 11 | ++++ | |
In Table 2 above, EC50 values are indicated as follows: <7000-500 nM ‘+’; <500-100 nM ‘++’; 10−<100 nM ‘+++’; <10 nM ‘++++’. | ||
All compounds tested exhibited EC50 values <2000 nM. |
Claims (8)
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US10364245B2 (en) * | 2017-06-07 | 2019-07-30 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
US10537560B2 (en) | 2017-10-05 | 2020-01-21 | Fulcrum Therapeutics. Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
US11291659B2 (en) | 2017-10-05 | 2022-04-05 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
US11479770B2 (en) | 2017-10-05 | 2022-10-25 | Fulcrum Therapeutics, Inc. | Use of p38 inhibitors to reduce expression of DUX4 |
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UA104677C2 (en) | 2014-02-25 |
IL223463A (en) | 2016-12-29 |
JP5791708B2 (en) | 2015-10-07 |
WO2011154738A1 (en) | 2011-12-15 |
AU2011263492A1 (en) | 2013-01-10 |
SG186228A1 (en) | 2013-01-30 |
US20130143914A1 (en) | 2013-06-06 |
EP2580212A1 (en) | 2013-04-17 |
GB201009731D0 (en) | 2010-07-21 |
RU2012153164A (en) | 2014-06-20 |
CA2802010A1 (en) | 2011-12-15 |
BR112012031226A2 (en) | 2018-03-06 |
RU2586223C2 (en) | 2016-06-10 |
JP2013528205A (en) | 2013-07-08 |
CN103140489B (en) | 2016-05-18 |
ZA201209289B (en) | 2014-02-26 |
EP2580212B1 (en) | 2015-01-28 |
KR20130086944A (en) | 2013-08-05 |
MX2012014371A (en) | 2013-01-29 |
AU2011263492B2 (en) | 2015-11-12 |
CN103140489A (en) | 2013-06-05 |
MY159239A (en) | 2016-12-30 |
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